New Delhi Metallo-β-lactamase-1 Producers Research Articles

Dissemination of Klebsiella pneumoniae ST147 NDM-1 in Poland, 2015-19.

To assess the spread of New Delhi metallo-β-lactamase-1 (NDM-1)-producing Klebsiella pneumoniae ST147 organisms in Poland since an introduction from Tunisia in March 2015, including their phylogenetic position in the global population of the high-risk clone. Out of 8925 unique NDM-positive K. pneumoniae isolates identified in Poland from April 2015 till December 2019, 126 isolates, including the Tunisian imports, were related by PFGE and blaNDM gene-carrying Tn125 transposon derivatives. Forty-seven representative isolates were sequenced by Illumina MiSeq. The phylogeny, resistome, virulome and plasmid replicons were analysed and compared with the international ST147 strains. Plasmids of six isolates were studied by the MinION sequencing. A high homogeneity of the 47 isolates was observed, with minor variations in their resistomes and plasmid replicon profiles. However, the detailed SNP comparison discerned a strict outbreak cluster of 40 isolates. All of the organisms were grouped within the ST147 phylogenetic international lineage, and four NDM-1 producers from Tunisia, Egypt and France were the closest relatives of the Polish isolates. Yersiniabactin genes (YbST280 type) were located within the ICEKpn12-like element in most of the outbreak isolates, characterized by O2v1 and KL64 antigen loci. The blaNDM-1 genes were located in double-replicon IncFIIK2+IncFIBK plasmids. The continuous spread of K. pneumoniae ST147 NDM-1 in Poland since 2015, largely in the Warsaw area, is demonstrated by this genomic analysis. The isolates showed a high degree of homogeneity, and close relatedness to organisms spreading in the Mediterranean region.

Discovery of thiosemicarbazone derivatives as effective New Delhi metallo-β-lactamase-1 (NDM-1) inhibitors against NDM-1 producing clinical isolates

New Delhi metallo-β-lactamase-1 (NDM-1) is capable of hydrolyzing nearly all β-lactam antibiotics, posing an emerging threat to public health. There are currently less effective treatment options for treating NDM-1 positive “superbug”, and no promising NDM-1 inhibitors were used in clinical practice. In this study, structure–activity relationship based on thiosemicarbazone derivatives was systematically characterized and their potential activities combined with meropenem (MEM) were evaluated. Compounds 19bg and 19bh exhibited excellent activity against 10 NDM-positive isolate clinical isolates in reversing MEM resistance. Further studies demonstrated compounds 19bg and 19bh were uncompetitive NDM-1 inhibitors with Ki = 0.63 and 0.44 μmol/L, respectively. Molecular docking speculated that compounds 19bg and 19bh were most likely to bind in the allosteric pocket which would affect the catalytic effect of NDM-1 on the substrate meropenem. Toxicity evaluation experiment showed that no hemolysis activities even at concentrations of 1000 mg/mL against red blood cells. In vivo experimental results showed combination of MEM and compound 19bh was markedly effective in treating infections caused by NDM-1 positive strain and prolonging the survival time of sepsis mice. Our finding showed that compound 19bh might be a promising lead in developing new inhibitor to treat NDM-1 producing superbug.

Oligopeptides as full-length New Delhi metallo-β-lactamase-1 (NDM-1) inhibitors.

‘Superbug’ bacteria producing NDM-1 enzyme causing wide public concern were first detected in a patient who visited India in 2008. It's an effective approach to combining β-lactam antibiotics with NDM-1 inhibitor for treating NDM-1 producing strain infection. In our research, we designed ten oligopeptides, tested IC50 values against NDM-1 enzyme, determined the MIC values of synergistic antibacterial effect and explored the binding model. We found that the oligopeptides 2 (Cys-Phe) and 5 (Cys-Asp) respectively presented IC50 values of 113 μM and 68 μM and also displayed favorable synergistic effects of the inhibitors in combination with ertapenem against genetic engineering-host E. coli BL21 (DE3)/pET30a-NDM-1 and a clinical isolate of P. aeruginosa with blaNDM-1. Flexible docking and partial charge study suggested the interaction between oligopeptide and NDM-1. Three types of action effects, hydrogen bond, electrostatic effect and π-π interaction, contributed to the inhibitory activities.

Emergence of Multidrug-Resistant New Delhi Metallo-β-Lactamase-1-Producing Klebsiella pneumoniae in Egypt.

Despite expansion of the New Delhi metallo-β-lactamase-1 (NDM-1) worldwide, the incident of outbreaks regarding Egypt is still uncommon. In this survey, we denounce the emanation of multidrug-resistant NDM-1-producing Klebsiella pneumoniae in Egypt. We have reclaimed 46 unrepeatable carbapenem-resistant K. pneumoniae isolates at El-demerdash hospital, Ain Shams University, Cairo, Egypt. All the isolates showed a decreased sensitivity to imipenem and meropenem via the disc diffusion method. Among the isolates, 10 were proven as NDM-1 producers by utilizing the phenotypic methods (modified Hodge test and EDTA synergistic test) and specific PCR detection of NDM-1 encoding gene, blaNDM-1. The isolates hosting the blaNDM-1 showed an elevated resistance to several classes of β-lactam and non β-lactam antibiotics. All blaNDM-1-harboring isolates have showed positivity for one or more other plasmid-mediated bla genes; in addition, the isolates carried class 1 integron. Enterobacterial repetitive intergenic consensus (ERIC)-PCR results revealed that majority of the isolates, including the NDM-1 producers, are unrelated to each other. This highlights the danger of horizontal transfer of plasmids encoding for such carbapenemases, including NDM-1, between the isolates of K. pneumoniae. In summary, this study has confirmed the incidence of blaNDM-1 together with other bla genes among the K. pneumoniae isolates in Egypt. Control and prevention of infection can be achieved through early detection of resistance genes among bacterial isolates; through limiting the dispersal of these organisms.

New Delhi metallo-β-lactamase-1: structure, inhibitors and detection of producers.

Since its discovery in 2008, New Delhi metallo-β-lactamase-1 (NDM-1)-producing Enterobacteriaceae have disseminated globally, facilitated predominantly by gut colonization and the spread of plasmids carrying the bla NDM-1 gene. With few effective antibiotics against NDM-1 producers, and resistance developing to those which remain, there is an urgent need to develop new treatments. To date, most drug design in this area has been focused on developing an NDM-1 inhibitor and has been aided by the wealth of structural and mechanistic information available from high resolution x-ray crystallography and molecular modeling. This review aims to summarize current knowledge regarding the detection of NDM-1 producers, the mechanism of action of NDM-1 and to highlight recent attempts toward the development of clinically useful inhibitors.

NDM-1–producing Strains, FamilyEnterobacteriaceae,in Hospital, Beijing, China

NDM-1–producing Strains, Family<i>Enterobacteriaceae,</i>in Hospital, Beijing, China

Co-Production of NDM-1 and OXA-232 byKlebsiella pneumoniae

Co-Production of NDM-1 and OXA-232 by<i>Klebsiella pneumoniae</i>

New Delhi Metallo-β-Lactamase-1 in Carbapenem-ResistantSalmonellaStrain, China

New Delhi Metallo-β-Lactamase-1 in Carbapenem-Resistant<i>Salmonella</i>Strain, China

Higher Isolation of NDM-1 Producing Acinetobacter baumannii from the Sewage of the Hospitals in Beijing

Multidrug resistant microbes present in the environment are a potential public health risk. In this study, we investigate the presence of New Delhi metallo-β-lactamase 1 (NDM-1) producing bacteria in the 99 water samples in Beijing City, including river water, treated drinking water, raw water samples from the pools and sewage from 4 comprehensive hospitals. For the bla NDM-1 positive isolate, antimicrobial susceptibility testing was further analyzed, and Pulsed Field Gel Electrophoresis (PFGE) was performed to determine the genetic relationship among the NDM-1 producing isolates from sewage and human, as well as the clinical strains without NDM-1. The results indicate that there was a higher isolation of NDM-1 producing Acinetobacter baumannii from the sewage of the hospitals, while no NDM-1 producing isolates were recovered from samples obtained from the river, drinking, or fishpond water. Surprisingly, these isolates were markedly different from the clinical isolates in drug resistance and pulsed field gel electrophoresis profiles, suggesting different evolutionary relationships. Our results showed that the hospital sewage may be one of the diffusion reservoirs of NDM-1 producing bacteria.

Evaluation of the double‐disk synergy test for New Delhi metallo‐β‐lactamase‐1 and other metallo‐β‐lactamase producing gram‐negative bacteria by using metal‐ethylenediaminetetraacetic acid complexes

New Delhi metallo-β-lactamase-1 (NDM-1), one of the metallo-β-lactamases (MBLs), has been identified from clinical isolates worldwide. Rapid detection of NDM-1 producers is necessary to prevent their dissemination. Seven types of EDTA complexes were evaluated as MBL inhibitors in double-disk synergy tests (DDSTs), resulting in detection of the first isolate of NDM-1-producing Escherichia coli (NDM-1 Dok01) in Japan. NDM-1 Dok01 was detected when EDTA magnesium disodium salt tetrahydrate (Mg-EDTA), EDTA calcium disodium salt dihydrate, EDTA cobalt disodium salt tetrahydrate and EDTA copper disodium salt tetrahydrate were used as MBL inhibitors. The sensitivity and specificity of DDSTs using Mg-EDTA for 75 MBL producers and 25 non-MBL producers were 96.0% and 100%, respectively. These findings indicate that the DDST method using Mg-EDTA can detect MBL-producing strains, including NDM-1 producers.

Spread of carbapenemase NDM-1 producers: The situation in India and what may be proposed

New Delhi metallo-β-lactamase 1 (NDM-1) producers, first identified from patients hospitalized in India, are now reported worldwide. The Indian subcontinent is clearly a main reservoir of NDM-1 producers. In order to slow down the spread of these NDM-1-positive Enterobacteriaceae, first in India and then worldwide, a series of measures must be implemented as soon as possible. These include discouraging the over-the-counter sale of antibiotics, improving basic and extended knowledge on hygiene, and the wide-scale detection of bla(NDM-1), in both infecting agents and in the carrier state for at-risk patients.

Nanodrugs: optimism for emerging trend of multidrug resistance

Nanodrugs: optimism for emerging trend of multidrug resistance Asad U KhanMedical Microbiology and Molecular Biology Laboratory, Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India This is with reference to an article published recently in your journal regarding the antibiotic activity of chitosan-coated silver nanoparticles.1 This is an inspiring move towards control of infection caused by multidrug-resistant bacteria which has become a serious problem for clinicians and physicians worldwide.2 At the moment, carbapenems are being used as the drugs of choice to combat infections. However, the emergence of carbapenem resistance has changed current remedial approaches in the management of serious infections. One of the latest enzymes, NDM-1 (New Delhi metallo-β-lactamase-1), first identified in a Swedish patient of Indian origin in 2008,3 has been key in the development of resistance to almost all antibiotics. Infection caused by NDM-1 producers is widespread on the Indian subcontinent,4 and is now emerging in the US and other countries throughout the world.5View original paper by Jena and colleagues.

Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study

SummaryBackgroundGram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1 (NDM-1) are potentially a major global health problem. We investigated the prevalence of NDM-1, in multidrug-resistant Enterobacteriaceae in India, Pakistan, and the UK.MethodsEnterobacteriaceae isolates were studied from two major centres in India—Chennai (south India), Haryana (north India)—and those referred to the UK's national reference laboratory. Antibiotic susceptibilities were assessed, and the presence of the carbapenem resistance gene blaNDM-1 was established by PCR. Isolates were typed by pulsed-field gel electrophoresis of XbaI-restricted genomic DNA. Plasmids were analysed by S1 nuclease digestion and PCR typing. Case data for UK patients were reviewed for evidence of travel and recent admission to hospitals in India or Pakistan.FindingsWe identified 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other sites in India and Pakistan. NDM-1 was mostly found among Escherichia coli (36) and Klebsiella pneumoniae (111), which were highly resistant to all antibiotics except to tigecycline and colistin. K pneumoniae isolates from Haryana were clonal but NDM-1 producers from the UK and Chennai were clonally diverse. Most isolates carried the NDM-1 gene on plasmids: those from UK and Chennai were readily transferable whereas those from Haryana were not conjugative. Many of the UK NDM-1 positive patients had travelled to India or Pakistan within the past year, or had links with these countries.InterpretationThe potential of NDM-1 to be a worldwide public health problem is great, and co-ordinated international surveillance is needed.FundingEuropean Union, Wellcome Trust, and Wyeth.